Pharmaceutical composition comprising loratadine, ibuprofen and pseudoephedrine

ABSTRACT

Pharmaceutical compositions for use in the treatment of cough/cold symptoms comprising loratadine, ibuprofen and pseudoephedrine are disclosed.

BACKGROUND OF THE INVENTION

The present invention relates generally to novel pharmaceuticalcompositions of matter comprising the non-sedating antihistamineloratadine or the decarbalkoxylation product thereof (i.e.6-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]-cyclohehepta[1,2-b]-pyridine),in combination with the non-steroidal anti-inflammatory drug ibuprofen,the decongestant pseudoephedrine, and suitable pharmaceuticallyacceptable non-toxic carriers or excipients, and to methods of usingsaid compositions in the treatment, management or mitigation of cough,cold, cold-like and/or flu symptoms and the discomfort, pain, fever andgeneral malaise associated therewith.

Non-narcotic analgesics, most of which are also known as non-steroidalanti-inflammatory drugs, such as ibuprofen, are widely administeredorally in the treatment of mild to severe pain, and have been disclosedas useful in treating cough/cold symptoms in combination with certainantihistamines and decongestants. See, for example U.S. Pat. Nos.4,552,899, 4,619,934 and 4,783,465, all to Sunshine et al.

SUMMARY OF THE INVENTION

It is a primary object of the present invention to provide a novelsustained release pharmaceutical composition of matter comprising acombination of an analgesically effective amount of ibuprofen, anantihistaminic-effective amount of loratadine and adecongestant-effective amount of pseudoephedrine in a pharmaceuticallyacceptable carrier.

It is a further object of the present invention to provide methods forthe symptomatic relief of cough, cold, cold-like and flu symptoms by theadministration of preselected dosages of the pharmaceutical compositionsof the present invention. Cold-like symptoms as used herein refers tocoryza, nasal congestion, upper respiratory infections, allergicrhinitis, otitis, sinusitis, etc.

DETAILED DESCRIPTION OF THE INVENTION

A combination dosage form especially suitable for administration of acombination comprising ibuprofen, loratadine or its decarbalkoxylationproduct, and pseudoephedrine or a pharmaceutically acceptable saltthereof is disclosed. The dosage form provides for the sustained releaseof ibuprofen and pseudoephedrine or a salt thereof, preferably thesulfate, and the immediate release of loratadine or itsdecarbalkoxylation product, since the latter are inherently long-acting.Release of ibuprofen and pseudoephedrine takes place over 2 to 16 hours,preferably 5 to 12 hours. One or two, preferably two tablets areadministered at a time. Concentration ranges for the actives are asfollows: pseudoephedrine salt, 30-240 mg/tablet; ibuprofen, 100-800mg/tablet; and loratadine or its decarbalkoxylation product, 0.5-10mg/tablet. The concentration ranges represent about 3 to about 25% ofcoated tablet weight for pseudoephedrine salt, about 10 to about 55% foribuprofen, and about 0.05 to about 1.5% for loratadine.

The preferred dosage form is a coated tablet, wherein loratadine or itsdecarbalkoxylation product is present in the tablet coating andibuprofen and the pseudoephedrine salt are present in the tablet core,which core also comprises a swellable hydrophilic polymer as a binder.When the dosage form comes into contact with gastric or aqueous media,the coating dissolves rapidly to release loratadine and the corehydrates and slowly releases ibuprofen and pseudoephedrine by erosion ofthe hydrated layer and/or by diffusion of drug through the core. Therate and duration of release is controlled by the relative concentrationof the hydrophilic polymer, as well as by the particular characteristicsof the hydrophilic polymer selected.

Loratadine, the USAN chemical name of which is ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate, is claimedin U.S. Pat. No. 4,282,233, and its decarbalkoxylation product,8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,claimed in U.S. Pat. No. 4,659,716. Pharmaceutically acceptable salts ofloratadine and its decarbalkoxylation product are also contemplated foruse in the present invention. The dosage range for both loratadine andits decarbalkoxylation product is about 0.5 to about 10 mg per day,preferably about 5 to about 10 mg/day, depending on the age, weight,condition, etc. of the patient.

Typical swellable hydrophilic polymers include cellulosic ethers such asmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, carboxymethylcellulose and carboxyethylcellulose,or mixtures thereof, with hydroxypropylmethylcellulose (HPMC) beingpreferred. Particularly useful HPMC polymers are HPMC USP 2910 and USP2208, for example The Dow Chemical Company's METHOCEL E4M, E15M andK100M, wherein the designation "E" refers to USP 2910 and thedesignation "K" refers to USP 2208, and wherein the number designationrefers to the viscosity in a 2% aqueous solution (e.g. 4M designates aviscosity of 4000 cps) and indicates the number average molecular weight(Mn) of the polymers (E4M has Mn 86,000, E15M has Mn 120,000, and K100Mhas Mn 246,000). The hydrophilic polymer or polymer mixture is presentat a concentration of about 5 to about 15% of the tablet core weight.

The tablet core optionally further comprises excipients such asinsoluble polymers, soluble or insoluble fillers, antiadherents,lubricants and additional binders. Typical fillers include dibasiccalcium phosphate and the dihydrate thereof, microcrystalline celluloseand lactose, with microcrystalline cellulose being preferred. Fillersare present at a concentration of about 10% to about 20% of the tabletcore weight. Antiadherents, used to prevent tablets from sticking to thetablet press, typically include silicas such as silicon dioxide andtalc, and are present at a concentration of 0 to about 5% of the tabletcore weight. Typical lubricants are magnesium stearate and stearic acid,present at a concentration of about 0.25 to about 5% of the tablet coreweight. Additional binders used in the granulation of the drug-polymermixture typically include povidone and cornstarch. Such binders arepresent at a concentration of about 0.5 to about 3% of the tablet coreweight.

The tablet coating comprises, in addition to the active, a hydrophilicpolymer as described above, preferably HPMC, and a plasticizer such aspolyethylene glycol (PEG). A preferred HPMC for tablet coating is HPMC2910 having a viscosity of 4-60 cps in a 2% aqueous solution, morepreferably having a viscosity of 6 cps. The PEG preferably has amolecular weight of 300-6000. The ratio of polymer to plasticizer isabout 2:1 to about 5:1, with 5:1 being preferred.

For preferred compositions of the present invention, either theibuprofen or the pseudoephedrine (or salt thereof) is also coated withHPMC-PEG as described for the tablet coating in order to avoid stabilityproblems arising from the physical incompatibility of ibuprofen andpseudoephedrine.

The methods of preparing compositions of the present invention, e.g.granulation, tablet compression and tablet coating, are all well knownto those skilled in the art.

    ______________________________________                                                            mg/tablet                                                 ______________________________________                                        A.       Core Tablet                                                                   Pseudoephedrine Sulfate                                                                        120                                                          Ibuprofen 90%*   555                                                          HPMC K100M       100                                                          Povidone         10                                                           Microcrystalline Cellulose                                                                     154                                                          HPMC/PEG         28                                                           Magnesium Stearate                                                                             5                                                                             972                                                 B.       Active Coating                                                                Loratadine       5                                                            HPMC/PEG         10                                                  ______________________________________                                         *Equivalent to 500 mg ibuprofen                                          

METHOD OF MANUFACTURE A. Core

1. Blend pseudoephedrine sulfate, microcrystalline cellulose and HPMCK100M for 5-30 minutes in a suitable mixer.

2. Dissolve povidone in a hydroalcoholic mixture and use it to granulatethe powder mix.

3. Dry and mill the pseudoephedrine sulfate granulation using suitablesize screen.

4. Coat ibuprofen with HPMC/PEG solution in a suitable coater (see partB below).

5. Blend the screened pseudoephedrine sulfate granulation with coatedibuprofen and remaining ingredients for 3-15 minutes.

6. Compress into suitable size tablets.

B. Ibuprofen coating

1. Dissolve HPMC and PEG in suitable amount of water.

2. Coat ibuprofen with the HPMC/PEG solution in a suitable coater.

C. Active Loratadine Coating

1. Dissolve HPMC/PEG in suitable amount of water or a water/alcoholmixture.

2. Disperse loratadine in the HPMC/PEG solution.

3. Coat tablets with the dispersion and polish the coated tablets usingstandard procedures.

    ______________________________________                                                            mg/tablet                                                 ______________________________________                                        A.       Core                                                                          Pseudoephedrine Sulfate                                                                        120                                                          Ibuprofen 90%*   555                                                          HPMC E4M         150                                                          Povidone         7.5                                                          Microcrystalline Cellulose                                                                     148.5                                                        Silicon Dioxide  14                                                           Magnesium Stearate                                                                             5                                                                             1000                                                B.       Coating                                                                       Loratadine       5                                                            HPMC/PEG         10                                                  ______________________________________                                         *Equivalent to 500 mg ibuprofen                                          

METHOD OF MANUFACTURE A. Core

1. Blend pseudoephedrine sulfate, microcrystalline cellulose and HPMCE4M for 5-30 minutes in a suitable mixer.

2. Dissolve povidone in a hydroalcoholic mixture and use it to granulatethe powder blend.

3. Dry and mill the pseudoephedrine sulfate granulation using suitablesize screen.

4. Blend the pseudoephedrine sulfate granulation, ibuprofen andremaining ingredients for 3-15 minutes.

5. Compress into suitable size tablets.

B. Active Loratadine Coating

1. Dissolve HPMC and PEG in suitable amount of water.

2. Disperse loratadine in the HPMC/PEG solution.

3. Coat tablets with the dispersion and polish the coated tablets usingstandard procedures.

A similar dosage form comprising the non-steroidal anti-inflammatorydrug acetaminophen in place of ibuprofen is also a part of the presentinvention. The dosage form releases acetaminophen and pseudoephedrineover 2 to 16 hours, preferably 5 to 12 hours, and immediately releasesloratadine. Concentration ranges for the actives are as follows:pseudoephedrine salt, 30-240 mg/tablet; acetaminophen, 100-500mg/tablet; and loratadine or its decarbalkoxylation product, 0.5-10mg/tablet. The concentration ranges represent about 3 to about 35% ofcoated tablet weight for pseudoephedrine salt, about 10 to about 65% foracetaminophen and about 0.05 to about 1.5% for loratadine.

The hydrophilic polymers are present at a concentration of about 5 toabout 15%, fillers at about 10 to about 20%, antiadherents at 0 to about5%, lubricants at 0.25 to about 5%, and binders at 0 to about 3%, allpercentages being relative to the tablet core weight.

The tablet coating comprises the loratadine or its decarbalkoxylationproduct, a hydrophilic polymer and a plasticizer as described above,i.e. a preferred polymer is HPMC USP 2910 and a preferred plasticizer isPEG, present in a preferred ratio of 5:1.

The following example is directed to a loratadine, acetaminophen andpseudoephedrine sulfate combination dosage form.

    ______________________________________                                                             mg/tablet                                                ______________________________________                                        A.      Core Tablet                                                                   Pseudoephedrine Sulfate                                                                          60                                                         Acetaminophen 90%* 555                                                        Dicalcium phosphate dihydrate                                                                    98                                                         HPMC E4M           48                                                         Stearic Acid       10                                                         Magnesium Stearate 4                                                                             775                                                B.      Active Coating                                                                Loratadine         2.5                                                        HPMC/PEG           5.0                                                ______________________________________                                         *Equivalent to 500 mg acetaminophen                                      

METHOD OF MANUFACTURE A. Core

1. Blend pseudoephedrine sulfate, acetaminophen, dicalcium phosphatedihydrate and HPMC E4M for 5-30 minutes in a suitable mixer.

2. Granulate the powder mix with a hydroalcoholic mixture.

3. Dry and mill the granulation using suitable size screen.

4. Compress into suitable size tablets.

B. Active Loratadine Coating

1. Dissolve HPMC/PEG in suitable amount of water or a water/alcoholmixture.

2. Disperse loratadine in the HPMC/PEG solution.

3. Coat tablets with the dispersion and polish the coated tablets usingstandard procedures.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit of the invention. Forexample, effective dosages of the active ingredients other than thepreferred ranges set forth hereinabove may be used based on such factorsas the age, weight and condition of the patient. It is intended that theinvention be limited only by the scope of the claims which follow.

We claim:
 1. A sustained release pharmaceutical composition comprising acoated tablet wherein the tablet coating comprises anantihistaminic-effective amount of loratadine or6-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridineand a hydrophilic polymer and the tablet core comprises ananalgesic-effective amount of ibuprofen, a decongestant-effective amountof pseudoephedrine or a pharmaceutically acceptable salt thereof and aswellable hydrophilic polymer, and wherein the tablet coating and thetablet core further comprise pharmaceutically acceptable excipients. 2.A composition of claim 1 wherein the tablet core comprises ibuprofen atabout 10 to about 55% of the coated tablet weight, pseudoephedrine or apharmaceutically acceptable salt thereof at about 3 to about 25% of thecoated tablet weight, and a hydrophilic polymer at about 5 to about 15%of the tablet core weight.
 3. A composition of claim 2 wherein thetablet core further comprises about 10 to about 20% filler, 0 to about5% antiadherent, about 0.25 to about 5% lubricant and about 0.5 to about3% binder.
 4. A composition of claim 2 wherein the hydrophilic polymeris a cellulosic ether selected from the group consisting ofmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, carboxymethylcellulose, carboxyethylcellulose andmixtures thereof.
 5. A composition of claim 3 wherein the filler isdibasic calcium phosphate or the dihydrate thereof, microcrystallinecellulose or lactose; the antiadherent is silicon dioxide or talc; thelubricant is magnesium stearate or stearic acid; and the binder ispovidone or cornstarch.
 6. A composition of claim 3 wherein thehydrophilic polymer is hydroxypropylmethylcellulose USP 2910 or ishydroxypropylmethylcellulose USP 2208 having a viscosity of 100,000 cpsin a 2% aqueous solution; the filler is microcrystalline cellulose; thelubricant is magnesium stearate; and the binder is povidone.
 7. Acomposition of claim 1 wherein the tablet coating comprises loratadineor6-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridineat a concentration of about 0.05 to about 1.5% of the coated tabletweight, and wherein the tablet coating further compriseshydroxypropylmethylcellulose and polyethylene glycol in a ratio of about2:1 to about 5:1.
 8. A composition of claim 7 wherein thehydroxypropylmethylcellulose is hydroxypropylmethyl cellulose USP 2910having a viscosity of 4-60 cps in a 2% aqueous solution, and thepolyethylene glycol has a molecular weight of 300-6000.
 9. A compositionof claim 1 wherein the tablet core comprises 120 mg pseudoephedrinesulfate, 555 mg ibuprofen 90%, 100 mg hydroxypropylmethylcellulose USP2208 having a viscosity of 100,000 cps in a 2% aqueous solution, 10 mgpovidone, 154 mg microcrystalline cellulose and 5 mg magnesium stearate,and wherein the tablet coating comprises 5 mg loratadine and 10 mg of a5:1 mixture of hydroxypropylmethylcellulose USP 2910 having a viscosityof 6 cps in a 2% aqueous solution and polyethylene glycol having amolecular weight of 300-6000.
 10. A composition of claim 9 wherein theibuprofen is coated with 28 mg of a 5:1 mixture ofhydroxypropylmethylcellulose USP 2910 having a viscosity of 6 cps in a2% aqueous solution and polyethylene glycol having a molecular weight of300-6000.
 11. A composition of claim 1 wherein the tablet core comprises120 mg pseudoephedrine sulfate, 555 mg ibuprofen 90%, 150 mghydroxypropylmethylcellulose USP 2910 having a viscosity of 4000 cps ina 2% aqueous solution, 75 mg povidone, 148.5 mg microcrystallinecellulose, 14 mg silicon dioxide and 5 mg magnesium stearate, andwherein the tablet coating comprises 5 mg loratadine and 10 mg of a 5:1mixture of hydroxypropylmethylcellulose USP 2910 having a viscosity of 6cps in a 2% aqueous solution and polyethylene glycol having a molecularweight of 300-6000.
 12. A method of treating cold, cold-like and flusymptoms comprising administering a composition of claim 1 to a mammalin need of such treatment.